chrX-100686087-C-T

Variant names:

• chrX-100686087-C-T
• rs766632925
• NM_001370165.1:c.1352G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_001370165.1(SYTL4):​c.1352G>A​(p.Arg451His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,208,578 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R451C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 5 hem.)
• Consequence: SYTL4 NM_001370165.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.38
• Publications: 1 publications found

Genes affected

SYTL4 (HGNC:15588): (synaptotagmin like 4) This gene encodes a member of the synaptotagmin like protein family. Members of this family are characterized by an N-terminal Rab27 binding domain and C-terminal tandem C2 domains. The encoded protein binds specific small Rab GTPases and is involved in intracellular membrane trafficking. This protein binds Rab27 and may be involved in inhibiting dense core vesicle exocytosis. Alternate splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Mar 2010]

SYTL4 Gene-Disease associations (from GenCC):

• retinal disorder

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370165.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYTL4	NM_001370165.1	MANE Select	c.1352G>A	p.Arg451His	missense	Exon 16 of 20	NP_001357094.1	Q96C24-1
	SYTL4	NM_001370162.1		c.1352G>A	p.Arg451His	missense	Exon 14 of 19	NP_001357091.1
	SYTL4	NM_001129896.3		c.1352G>A	p.Arg451His	missense	Exon 14 of 18	NP_001123368.1	Q96C24-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYTL4	ENST00000372989.6	TSL:1 MANE Select	c.1352G>A	p.Arg451His	missense	Exon 16 of 20	ENSP00000362080.1	Q96C24-1
	SYTL4	ENST00000276141.10	TSL:1	c.1352G>A	p.Arg451His	missense	Exon 13 of 17	ENSP00000276141.6	Q96C24-1
	SYTL4	ENST00000263033.9	TSL:2	c.1352G>A	p.Arg451His	missense	Exon 13 of 17	ENSP00000263033.5	Q96C24-1

Frequencies

GnomAD3 genomes AF: 0.0000446 AC: 5 AN: 111997 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000943

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00132

GnomAD2 exomes AF: 0.0000224 AC: 4 AN: 178848 AF XY: 0.0000315

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000135

Gnomad EAS exome AF: 0.000147

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 9 AN: 1096581 Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 5 AN XY: 362031

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26387

American (AMR) AF: 0.0000285 AC: 1 AN: 35123

Ashkenazi Jewish (ASJ) AF: 0.0000517 AC: 1 AN: 19359

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30165

South Asian (SAS) AF: 0.00 AC: 0 AN: 53643

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40461

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 841267

Other (OTH) AF: 0.0000434 AC: 2 AN: 46040

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000266003), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000446 AC: 5 AN: 111997 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34185

African (AFR) AF: 0.0000325 AC: 1 AN: 30773

American (AMR) AF: 0.0000943 AC: 1 AN: 10605

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3565

South Asian (SAS) AF: 0.00 AC: 0 AN: 2668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6091

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53212

Other (OTH) AF: 0.00132 AC: 2 AN: 1513

Alfa AF: 0.000174 Hom.: 2

Bravo AF: 0.0000302

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.72
MVP		0.32
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.96
gMVP		0.59
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs766632925; hg19: chrX-99941084;